Antimicrobial or antibiotic agents are widely used to treat as well as to prevent infection. In particular, silver is known to be antimicrobial and has been used (primarily as a coating) in various medical devices with limited success. Both active (e.g., by application of electrical current) and passive (e.g., galvanic) release of silver ions have been proposed for use in the treatment and prevention of infection. However, the use of silver-releasing implants have been limited because of the difficulty in controlling and distributing the release of silver ions as well as the difficulty in maintaining a therapeutically relevant concentration of silver ions in an appropriate body region. Zinc shares many of the same antimicrobial properties of silver, but has been less commonly used, and thus even less is known about how to control the amount and distribution of the release of silver ions to treat and/or prevent infection.
It would be highly beneficial to use an antimicrobial agent such as silver and/or zinc as part of an implant, including a bioabsorbable implant, in part because the risk of acquiring infections from bioabsorbable materials in medical devices is very high. Many medical applications exist for bioabsorbable materials including: wound closure (e.g., sutures, staples, adhesives), tissue repair (e.g., meshes, such as for hernia repair), prosthetic devices (e.g., internal bone fixation devices, etc.), tissue engineering (e.g., engineered blood vessels, skin, bone, cartilage, liver, etc.) and controlled drug delivery systems (such as microcapsules and ion-exchange resins). The use of bioabsorbable materials in medical applications such as these may reduce tissue or cellular irritation and the induction of an inflammatory response.
Bioabsorbable materials for medical applications are well known. For example, synthetic bioabsorbable polymers may include polyesters/polylactones such as polymers of polyglycolic acid, glycolide, lactic acid, lactide, dioxanone, trimethylene carbonate etc., polyanhydrides, polyesteramides, polyortheoesters, polyphosphazenes, and copolymers of these and related polymers or monomers, as well as naturally derived polymers such as albumin, fibrin, collagen, elastin, chitosan, alginates, hyaluronic acid; and biosynthetic polyesters (e.g., 3-hydroxybutyrate polymers). However, like other biomaterials, bioabsorbable materials are also subjected to bacterial contamination and can be a source of infections which are difficult to control. Those infections quite often require their removal and costly antimicrobial treatments.
Efforts to render bioabsorbable materials more infection resistant generally have focused on impregnating the materials with antibiotics or salts such as silver salts, and have provided only limited and instantaneous antimicrobial activity. It is desirable to have an antimicrobial effect which is sustained over time, such that the antimicrobial effect can be prolonged for the time that the bioabsorbable material is in place. This can range from hours or days, to weeks or even years.
Further, although antimicrobial/antibacterial metal coatings on medical devices have been suggested, metal coatings (such as silver or copper coatings) have not been characterized or optimized. In such applications, it is important that the metal coatings do not shed or leave behind large metal particulates in the body, which may induce unwanted immune responses and/or toxic effects. Further, it is essential that the release of the antimicrobial agent (metal) be metered over the lifetime of the implant.
For example, U.S. Pat. No. 8,309,216 describes substrates including degradable polymers that include an electron donor layer (such as silver, copper or zinc) onto which particles of palladium and platinum, plus one other secondary metal (chosen from gold, ruthenium, rhodium, osmium, iridium, or platinum) are deposited onto. Although such materials are described for anti-microbial implants (e.g., pacemakers, etc.), the separate layers formed by this method would be problematic for antimicrobial coatings in which the undercoating of silver, copper or zinc were being released, potentially undermining the platinum and secondary metal.
Similarly, U.S. Pat. No. 6,719,987 describes bioabsorbable materials having an antimicrobial metal (e.g., silver) coating that can be used for an implant. The silver coating is for release of particles (including ions) and must be in a crystalline form characterized by sufficient atomic disorder. In this example, the silver is also deposited in one or more layers. U.S. Pat. No. 6,080,490 also describes medical devices with antimicrobial surfaces that are formed by layers of metals (e.g., silver and platinum) to release ions; layers are etched to expose regions for release. The outer layer is always Palladium (and one other metal), beneath which is the silver.
Thus, it would be highly desirable to provide devices, systems and methods for the controlled release (particularly the controlled galvanic release) of a high level of silver, zinc or silver and zinc ions from a bioabsorbable material into the tissue for a sufficient period of time to treat or prevent infection.
Known systems and devices, including those described above, that have attempted to use ions (e.g., silver and/or zinc) on bioabsorbable materials to treat infection have suffered from problems such as: insufficient amounts of ions released (e.g., ion concentration was too low to be effective); insufficient time for treatment (e.g., the levels of ions in the body or body region were not sustained for a long enough period of time); and insufficient region or volume of tissue in which the ion concentration was elevated (e.g., the therapeutic region was too small or limited, such as just on the surface of a device). Further, the use of galvanic release has generally been avoided or limited because it may effectively corrode the metals involved, and such corrosion is generally considered an undesirable process, particularly in a medical device.
There is a need for antimicrobial coatings for substrates generally. Antimicrobial coatings may be useful for any surface that will be exposed to a conductive fluid, including blood, sweat, lymph, etc., whether implanted or not. For example, there is a particular need for antimicrobial coatings for bioabsorbable materials, which can create an effective and sustainable antimicrobial effect, which do not interfere with the bioabsorption of the bioabsorbable material, and which do not shed or leave behind large metal particulates in the body as the bioabsorbable material disappears.
Therapeutically, the level of silver and/or zinc ions released into a body is important, because it may determine how effective the antimicrobial ions are for treating or preventing infection. As described in greater detail below, the amount or ions released galvanically may depend on a number of factors which have not previously been well controlled. For example, galvanic release may be related to the ratio of the anode to the cathode (and thus, the driving force) as well as the level of oxygen available; given the galvanic reaction, the level of oxygen may be particularly important for at the cathode. Insufficient oxygen at the cathode may be rate-limiting for galvanic release.
For example, with respect to silver, it has been reported that a concentration of 1 mg/liter of silver ions can kill common bacteria in a solution. Silver ions may be generated a galvanic system with silver as the anode and platinum or other noble metal as the cathode. However one of the challenges in designing a galvanic system for creation of silver ion in the body that has not been adequately addressed is the appropriate ratios of the areas of the electrodes (e.g., anode to cathode areas) in order to create the germicidal level of free silver ions. One challenge in designing a galvanic system is addressing the parasitic loss of current due to formation of silver chloride via reaction:AgCl+e→Ag+Cl(−) Eo=0.222 volts
We herein propose that it may be beneficial to have an area of the cathode under common biological condition that is at least larger than 8% of the silver area to sustain the germicidal level of silver ions. For the purpose of this discussion, the following assumptions have been made: for a concentration of: [H+]=10^(−7) moles/liter; [OH−]=10^(−7) moles/liter; [O2]=5*10^(−3) moles/liter in the capillary; [Cl−]=0.1 moles/liter. The values of the following were also assumed (as constants or reasonable approximations): Faraday's constant, F=96000 coulombs/mole; diffusivity of oxygen=0.000234 cm2/sec; diffusivity of Ag+=10^(−6) cm2/sec; diffusivity of Cl−=10^(−6) cm2/sec; R, Gas constant=8.314 J K−1 mol−1; T, temp. K; Mw of silver=108 grams/mol; germicidal concentration of silver=10^(−5) mol/liter.
At equilibrium, for a galvanic cell it is acceptable to assume that the two electrodes are at the same potential. Using the Nernst equation, the equilibrium concentration of oxygen when the silver ion is at the germicidal level may be calculated:E=Eo−(RT/nF)ln [(Activity of products)/(activity of reactants)]E=Eo−(0.0592/n) Log [(product)/(reactant)]
For the half cell reaction at the anode (silver electrode): Ag→Ag(+)+e(−). This reaction is written as a reduction reaction below:Ag(+)+e(−)→Ag Eo=0.800 volt eq.  (1)
[Ag+]=1 mg/liter*(gr/1000 mg)*(1 mol/108 (Mw of Ag))=10^(−5) Ag+ mole/liter; E=0.800−(0.0592/1) log [1/(10^(−5)]. Based on this, the resulting E=8.00−(0.0592*5)=0.504 volt.
For the cathode, the reactions are:O2+2H2O+4e(−)→OH(−) Eo=0.401 volt eq.  (2)O2+4H(+)+4e(−)→2H2O Eo=1.229 volt eq.  (3)
In dilute aqueous solutions these two reactions are equivalent. At equilibrium the potential for the two half-cell potentials must be equal:E=0.401−(0.0592/4) log {[OH(−)]^4/[O2]}E(silver)=0.504=0.401−(0.0592/4) log {[10^−7]^4/[O2]}
Solving for [O2], the result is: [O2]=10^(−21) atm. The result of this analysis is that, thermodynamically speaking, as long as the concentration of oxygen is above 10^(−21), the concentration of the sliver ion could remain at the presumed germicidal level.
However, a parasitic reaction to creation of silver ions is the formation of AgCl due to reaction of Cl− at the silver electrode. The half-cell potential for this reaction is:AgCl+e(−)→Ag+Cl(−) Eo=0.222
Solving the Nernst equation for this reaction with E=0.504, the concentration of chloride [Cl−]=2×10^(−5). The importance of this reaction becomes apparent in evaluating the current needed to compensate for the losses of current due to this reaction and the increased in ratio of the area of the cathode to the anode.
The current density per until area requirements of the device can be estimated by combining Fick's and Faraday equations: the silver losses due to diffusion of silver from the device can be calculated using the Fick's equation:j=D[C(d)−C(c)]/d  Fick's equation
The current needed to create the silver ions (A/cm2): i=j*n*F, where, j is the mass flux, C(d) is the concentration of the silver at the device and C(c) is concentration of silver at the capillary bed (=0). D is the diffusion coefficient of silver (10^(−6)) cm2/sec, d is the average distance of the device from the capillary bed (assumed to be=0.5 cm in the bone), F is Faraday's constant (96000 col./mol), and n is the charge number.
The combination of the two equations for silver diffusion gives:i(Ag)=D*·n·F(C(d))/d 
Thus:
                              i          ⁡                      (            Ag            )                          =                  {                                    10              ^                              (                                  -                  6                                )                                      *            1            *                          (                              10                ^                                  (                                      -                    5                                    )                                            )                        *                          (              96000              )                        *                                                                                            ⁢                                    (                              5                *                                  10                  ^                                      (                                          -                      3                                        )                                                              )                        /            0.5                    }                *                  (                      1            ⁢                                                  ⁢            liter            ⁢                          /                        ⁢            1000            ⁢                                                  ⁢            cc                    )                                                                  ⁢                  =                      2            *                          10              ^                              (                                  -                  9                                )                                      ⁢                                                  ⁢            Amp            ⁢                          /                        ⁢                          cm              2                                          
The current needed to create the silver ions at the desired concentration is approximately 2 nanoAmp/cm2. Similarly, the current density (A/cm2) required to reduce the chloride ions from biological level (0.1 molar) to the desired level of 2*10^(−5) molar could be calculated. For this equation the approximate values of the constants are D=10^(−6), d=0.1 cm. The change in the Chloride concentration it assumed to be (0.1−2*10^(−5))=0.1. The current needed to feed the parasitic reaction can then be determined:
                              i          ⁡                      (            cl            )                          =                              {                                          (                                  10                  ^                                      (                                          -                      6                                        )                                                  )                            *                              (                1                )                            *                              (                96000                )                            *                                                (                  0.1                  )                                /                                  (                  0.1                  )                                                      }                    *                      (                          1              ⁢              lit              ⁢                              /                            ⁢              1000              ⁢                                                          ⁢              cc                        )                                                  =                  9.6          *                      10            ^                          (                              -                5                            )                                                              =                  96          ⁢                                          ⁢          microAmp          ⁢                      /                    ⁢                      Cm            2                              
The total anodic current needed is: i(Ag)+i(Cl)=i(anodic)=96 microAmps/cm2. On the cathode, the reaction limitation is the flux of oxygen form the source to the surface of the electrode. The max i(cathodic) current could be approximated to:
                              i          ⁡                      (                          O              ⁢                                                          ⁢              2                        )                          =                  {                                    (              0.000324              )                        *                          (              4              )                        *                          (              96000              )                        *                                                                                            ⁢                                    (                              5                *                                  10                  ^                                      (                                          -                      3                                        )                                                              )                        /            0.5                    }                *                  (                      1            ⁢                                                  ⁢            liter            ⁢                          /                        ⁢            1000            ⁢                                                  ⁢            cc                    )                                                                  ⁢                  =                      1.24            *                          10              ^                              (                                  -                  3                                )                                      ⁢                                                  ⁢                          Amp              ⁢              s                        ⁢                          /                        ⁢                          cm              2                                          
Since the total cathodic current must be equal to total Anodic current:i(cathodic)*Area of the cathode=i(anodic)*Area of Anode=>Area of the Cathode/Area of the anode=(96*10^(−6)/(1.24*10^(−3))=0.077
This suggests that the area of the cathode must be at least equal to 8% of that of anode.
In addition to the ratio of the cathode to the ratio of the anode, another factor affecting the release of silver ions that has not previously been accounted for in galvanic release of silver to treat infection is the concentration of oxygen needed.
The concentration of the oxygen needed to power the galvanic system is typically higher than that of the equilibrium concentration, since the system must overcome the activation energy of the reactions (over-potential) and supply the additional current. In the model below we evaluated the concentration of the oxygen needed to overcome the activation energy for the reactions. Using the Tafel equation:η=β log [i/io]
where i=current density, η=the over-potential, β=overpotential voltage constant, and io=intrinsic current density. For platinum, the oxygen over-potential constants are: β=0.05 volt and io=10^(−9) A/m2. Using i=9.6*10^(−5) Amp then:η=0.05 log [9.6*10^(−5)/(10^(−9))]η=0.25 volt
Adding the over potential to the potential at the equilibrium (0.501 volts), and the total working half-potential needed at the cathode becomes equal to (0.501+0.25)=0.751.
Using the Nernst equation to determine the concentration of oxygen at the cathode:E=0.751=0.401−(0.0592/4) log {[OH(−)]^4/[O2]}
Thus, the concentration of oxygen at the electrode should be at least 7*10^ (−5) mole.
The results of this analysis show that an implanted galvanic system would benefit from having an area of the cathode to the area of the anode (Acathode/Aanode) of greater that about 8% and the concentration of the oxygen at the site of implant to be at least 7*10^(−5) moles per liter, which may avoid rate-limiting effect.
Thus, to address the problems and deficiencies in the prior art mentioned above, described herein are systems, methods and devices (and in particular coatings, methods of coatings) for substrates that controllably release antimicrobial metal ions, including apparatuses (e.g., devices and/or systems) and methods for prevent infection and for eliminating existing infections. The coatings described herein may be used as part of any appropriate substrate, including medical devices (both implanted, inserted, and non-implanted/inserted medical devices), and non-medical devices including hand-held articles. In some particular examples, described below are implants including bioabsorbable substrates, and methods for using them.